Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:6.3.2.19 (ubiquitin-protein ligase)
 799 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The tumor suppressor p53 is a labile protein whose level is known to be regulated by the Mdm-2-ubiquitin-proteasome degradation pathway. We have found another pathway for p53 proteasomal degradation regulated by NAD(P)H quinone oxidoreductase 1 (NQO1). Inhibition of NQO1 activity by dicoumarol induces p53 and p73 proteasomal degradation. A mutant p53 (p53([22,23])), which is resistant to Mdm-2-mediated degradation, was susceptible to dicoumarol-induced degradation. This finding indicates that the NQO1-regulated proteasomal p53 degradation is Mdm-2-independent. The tumor suppressor p14(ARF) and the viral oncogenes SV40 LT and adenovirus E1A that are known to stabilize p53 inhibited dicoumarol-induced p53 degradation. Unlike Mdm-2-mediated degradation, the NQO1-regulated p53 degradation pathway was not associated with accumulation of ubiquitin-conjugated p53. In vitro studies indicate that dicoumarol-induced p53 degradation was ubiquitin-independent and ATP-dependent. Inhibition of NQO1 activity in cells with a temperature-sensitive E1 ubiquitin-activating enzyme induced p53 degradation and inhibited apoptosis at the restrictive temperature without ubiquitination. Mdm-2 failed to induce p53 degradation under these conditions. Our results establish a Mdm-2- and ubiquitin-independent mechanism for proteasomal degradation of p53 that is regulated by NQO1. The lack of NQO1 activity that stabilizes a tumor suppressor such as p53 can explain why humans carrying a polymorphic inactive NQO1 are more susceptible to tumor development.
 ...
PMID:Mdm-2 and ubiquitin-independent p53 proteasomal degradation regulated by NQO1. 1223 53

The tumor suppressor p53 is a short-lived protein that under normal conditions is reduced to a barely detectable level. The stability of p53 protein is primarily regulated in normal non-transformed cells by two interplayers: Mdm2 and p14(ARF). Relocation of p53, Mdm2, and p14(ARF) to the nucleolus seems to regulate, at least partially, the steady-state of p53. Moreover, there are alternative pathways of the regulation of p53 stability in unstressed cells. Jun-N(amino)-terminal kinase (JNK) and poly(ADP-ribose) polymerase-1 (PARP-1) are involved in the regulation of the steady-state of wild-type (wt) p53 protein. However, in most human cervical carcinomas, which express the high-risk human papilloma viruses (HPVs) E6 protein, a complete switch from Mdm2 to HPV E6-mediated degradation of p53 occurs. Virally encoded E6 protein utilizes the cellular ubiquitin-protein ligase termed E6-associated protein (E6-AP) to target p53 protein for proteolytic degradation. We recently addressed the question of whether p53 protein can be generally reactivated by chemotherapy in HeLa cells despite the E6 activity. We observed an increase of cellular p53 after cisplatin (CP) treatment. p53 protein accumulated preferentially in the nucleoli. We checked the cellular level of E6 during CP therapy. Six hours after application of CP the expression of E6 protein was markedly reduced. This coincided with the increase of cellular p53 level and preceded the nucleolar accumulation of p53 protein, thereby indicating that repression of virally coded E6 protein by CP contributes to the restoration of p53 expression.
 ...
PMID:How the nucleolar sequestration of p53 protein or its interplayers contributes to its (re)-activation. 1503 32

Collaborator of alternative reading frame protein (CARF) associates directly with ARF, p53, and/or human double minute 2 protein (HDM2), a ubiquitin-protein ligase, without cofactors and regulates cell proliferation by forming a negative feedback loop. Although ARF, p53, and HDM2 also participate in the regulation of ribosome biogenesis, the involvement of CARF in this process remains unexplored. In this study, we demonstrate that CARF associates with 5'-3' exoribonuclease 2 (XRN2), which plays a major role in both the maturation of rRNA and the degradation of a variety of discarded pre-rRNA species. We show that overexpression of CARF increases the localization of XRN2 in the nucleoplasm and a concomitant suppression of pre-rRNA processing that leads to accumulation of the 5' extended from of 45S/47S pre-rRNA and 5'-01, A0-1 and E-2 fragments of pre-rRNA transcript in the nucleolus. This was also observed upon XRN2 knockdown. Knockdown of CARF increased the amount of XRN2 in the nucleolar fraction as determined by cell fractionation and by immnocytochemical analysis. These observations suggest that CARF regulates early steps of pre-rRNA processing during ribosome biogenesis by controlling spatial distribution of XRN2 between the nucleoplasm and nucleolus.
...
PMID:Collaborator of alternative reading frame protein (CARF) regulates early processing of pre-ribosomal RNA by retaining XRN2 (5'-3' exoribonuclease) in the nucleoplasm. 2653 22